Glycyrrhiza uralensis Fisch. attenuates Dioscorea bulbifera L.-induced liver injury by regulating the FXR/Nrf2-BAs-related proteins and intestinal microbiota

Ethnopharmacological relevance: Dioscorea bulbifera L. (DBL) was a traditional Chinese medicine commonly used to treat goitre and cancer. Nevertheless, its clinical application may lead to liver injury. Glycyrrhiza uralensis Fisch. (GRR) was primarily utilized in traditional Chinese medicine for its ability to harmonize various medicines and mitigate the toxic effects of poisonous herbs. However, the role of GRR in mitigating the liver toxicity of DBL has not been established after combination.

Aim of the study: This study aimed to clarify the protective effect of GRR against DBL-induced liver injury in mice and investigate its mechanisms of action.

Materials and methods: 75% ethanol was employed to extract DBL and GRR. The extracted components were characterized using LC-MS. Mice were orally gavaged with extracts from each group for 30 days. After the experiment, the pathological changes in the liver of mice were evaluated. Additionally, biochemical markers associated with liver injury were assessed. The primary mechanisms through which GRR mitigates DBL-induced liver injury and the modulation of the liver-intestinal axis by GRR were explored utilizing untargeted metabolomics, targeted BAs metabolomics and 16S rDNA analyses. Furthermore, western blot and qPCR assessed the protein and mRNA transcription of the farnesoid X receptor (FXR) and nuclear factor-erythroid 2-related factor 2 (Nrf2) as well as BA-related transporters.

Results: GRR dose-dependently attenuated DBL-induced liver injury in mice. It mitigated hepatic pathological changes and alleviated hepatic inflammation and oxidative stress. GRR improved metabolic disorders induced by DBL in mice at the metabolite level, focusing on the ABC transporter. Moreover, GRR may be attributed to its activation of FXR/Nrf2 expression, reduction of cholesterol 7-alpha hydroxylase (CYP7A1) expression, promotion of bile salt export pump (BSEP), multi-drug resistance protein 2 (MRP2), P-glycoprotein (P-gp) and sodium taurocholate cotransport polypeptide (NTCP) expression, reduction of bile acid (BA) synthesis, promotion of BA efflux and reabsorption, and improvement of BA metabolic disorders. In addition, GRR ameliorated DBL-induced intestinal barrier injury and improved the structural organization of the intestinal flora, restoring the overall composition of the intestinal microbiota.

Conclusion: GRR exhibited significant alleviation of DBL-induced liver injury, potentially by modulating FXR/Nrf2-BA-related proteins, reducing hepatic BA accumulation, mitigating liver inflammation and oxidative stress, and regulating intestinal flora.